腫瘤十大特征綜述

1、Paper sharing:Hanahan D, Weinberg R. Hallmarks of Cancer: The Next Generation.Cell, 2011,144( 5): 646-674.Dept. Medical Oncology, 1st Affiliated Hospital*UniversitySix hallmarks of cancer proposed in 2000Emerging hallmarks Sustaining Proliferative Signaling The most fundamental trait of cancer cells

2、 involves their ability to sustain chronic proliferation Normal tissues ensuring a homeostasis by carefully control thing the production and release of growth-promoting signals Cancer cells, by deregulating these signals, become masters of their own destinies. The enabling signals are conveyed in la

3、rge part by growth factors that bind cell-surface receptors Cancer cells can acquire the capability to sustain proliferative signaling in a number of alternative ways Cancer cells can produce growth factor ligands Send signals to stimulate normal cells within the supporting tumor-associated stroma E

4、levating the levels of receptor proteins displayed at the cancer cell surface Structural alterations in the receptor molecules Somatic mutations activate additional downstream pathways. EGFR mutation in NSCLC, B-Raf mutation in melanoma. Disruptions of negative-feedback mechanisms that attenuate pro

5、liferative signaling Excessive proliferative signaling can trigger cell senescence: RAS,MYC.Evading Growth Suppressors Cancer cells must circumvent powerful programs that negatively regulate cell proliferation Many of these programs depend on the actions of tumor suppressor genes Two prototypical tu

6、mor suppressors encode the RB and TP53 proteins To remove contact Inhibition Corruption of the TGF-b Pathway Promotes Malignancy, more elaborate than simple shutdown of its antiproliferative signaling circuitry activate EMT The RB protein integrates signals from diverse extracellular and intracellul

7、ar sources and, in response, decides whether or not a cell should proceed through its growth-and-division cycleCancer cells with defects in RB pathway function are missing the services of a critical gatekeeper of cell-cycle progression whose absence permits persistent cell proliferation. TP53 receiv

8、es inputs from stress and abnormality sensors If the degree of damage to the genome is excessive, or if the levels of nucleotide pools, growth-promoting signals, glucose, or oxygenation are suboptimal, TP53 can call a halt to further cell-cycle progression until these conditions have been normalized

9、. Alternatively, in the face of alarm signals indicating overwhelming or irreparable damage to such cellular subsystems, TP53 can trigger apoptosis. Contact Inhibition the cell-to- cell contacts formed by dense populations of normal cells propagated in two-dimensional culture operate to suppress fur

10、ther cell proliferation, yielding confluent cellmonolayers. “contact inhibition” is abolished in various types of cancer cells in culture, suggesting that contact inhibition is an in vitro surrogate of a mechanism that operates in vivo to ensure normal tissue homeostasis Mechanisms of Contact Inhibi

11、tion the NF2 gene Merlin, the cytoplasmic gene product, orchestrates contact inhibition via coupling cell-surface adhesion molecules .Merlin strengthens the adhesivity of cadherin-mediated cell-to-cell attachments, by sequestering growth factor receptors, Merlin limits their ability to efficiently e

12、mit mitogenic signals LKB1 epithelial polarity protein which organizes epithelial structure and helps maintain tissue integrity overrule the mitogenic effects of the powerful Myc oncogene LKB1 expression is suppressed, epithelial integrity is destabilized, and epithelial cells become susceptible to

13、Myc-induced transformationResisting Cell Death Apoptosis Autophagy NecrosisApoptosis The concept that apoptosis serves as a natural barrier to cancer development has been established over the last two decades Apoptosis is attenuated in those tumors that succeed in progressing to states of high-grade

14、 malignancy and resistance to therapy The apoptotic machinery is composed of both upstream regulators and downstream effector components The regulators are divided into two major circuits, one receiving and processing extracellular death-inducing signals (the extrinsic apoptotic program, for example

15、 the Fas ligand/Fas receptor) The other sensing and integrating a variety of signals of intracellular origin (the intrinsic program). Apoptosis signaling pathways Apoptosis-triggering mechanisms TP53 induces in response to substantial levels of DNA breaks and other chromosomal abnormalities. insuffi

16、cient survival factor signaling , interleukin-3, IGF-1 Hyperactive signaling by certain oncoproteins, such as MycStrategies developed by cancer cells to circumvent apoptosis Most common is the loss of TP53 tumor suppressor function Increasing expression of antiapoptotic regulators (Bcl-2, Bcl-xL) or

17、 of survival signals Downregulating proapoptotic factors (Bax, Bim, Puma), or by short-circuiting the extrinsic ligand-induced death pathwayAutophagy Can be strongly induced in certain states of cellular stress, the most obvious of which is nutrient deficiency In this fashion, low-molecular-weight m

18、etabolites are generated that support survival in the stressed, nutrient-limited environments experienced by many cancer cellsAutophagy is cytoprotective for cancer cells Nutrient starvation, radiotherapy, and certain cytotoxic drugs can induce elevated levels of autophagy Severely stressed cancer c

19、ells have been shown to shrink via autophagy to a state of reversible dormancy This survival response may enable the persistence and eventual regrowth of some late stage tumors following treatment with potent anticancer agents.Necrosis Has Proinflammatory and Tumor-Promoting Potential Necrotic cells

20、 releasing their contents into the local tissue microenvironment Immune inflammatory cells can be actively tumor promoting, given that such cells are capable of fostering angiogenesis, cancer cell proliferation, and invasiveness Necrotic cells can release bioactive regulatory factors, such as IL-1aE

21、nabling Replicative ImmortalityMost normal cell lineages are able to pass through only a limited number of successive cell growth-and-division cycles. This limitation has been associated with two distinct barriers to proliferation senescence, a typically irreversible entrance into a nonproliferative

22、 but viable state, crisis, in which the great majority of cells in the population die.Cancer cells :able to proliferate in culture without evidence of either senes- cence or crisis (immortalization)Telomeres protecting the ends of chromosomes are centrally involved in the capability for unlimited pr

23、oliferationThe telomeres, composed of multiple tandem hexanucleotide repeats, shorten progressively in nonimmortalized cells propagated in culture, eventually losing the ability to protect the ends of chromosomal DNAs from end-to-end fusions Telomerase, the specialized DNA polymerase that adds telom

24、ere repeat segments to the ends of telomeric DNA, is almost absent in nonimmortalized cells but expressed at functionally significant levels in the vast majority ( 90%) of immortalized cells, including human cancer cells Expression of the enzyme is correlated with a resistance to induction of both s

25、enescence and crisis/apoptosis Suppression of telomerase activity leads to telomere shortening and to activation of one or the other of proliferative barriers. Delayed Activation of Telomerase May Both Limitand Foster Neoplastic Progression Clones of incipient cancer cells often experience telomere

26、loss-induced crisis relatively early during the course of multistep tumor progression due to their inability to express signficant levels of telomerase. The absence of TP53-mediated surveillance of genomic integrity may permit other incipient neoplasias to survive initial telomere erosion and attend

27、ant chromosomal breakage-fusion-bridge (BFB) cycles. Overt carcinomas exhibited telomerase expression concordantly with the reconstruction of longer telomeres and the fixation of the aberrant karyotypes . The delayed acquisition of telomerase function serves to generate tumor-promoting mutations, wh

28、ereas its subsequent activation stabilizes the mutant genome and confers the unlimited replicative capacityInducing Angiogenesis Tumors require sustenance in the form of nutrients and oxygen as well as an ability to evacuate metabolic wastes and carbon dioxide. The process of angiogenesis, addresses

29、 these needs. The normal vasculature becomes largely quiescent. In the adult, as part of physiologic processes such as wound healing and female reproductive cycling, angiogenesis is turned on, but only transientlyangiogenesis precocious capillary sprouting convoluted and excessive vessel branching,

30、distorted and enlarged vessels, erratic blood flow, microhemorrhaging, leakiness, abnormal levels of endothelial cell proliferation and apoptosis During tumor progression, an “angiogenic switch” is almost always activated and remains on, causing normally quiescent vasculature to continually sprout n

31、ew vessels that help sustain expanding neoplastic growths The angiogenic switch is governed by countervailing factors that either induce or oppose angiogenesis VEGF-Athree receptor tyrosine kinases(VEGFR-13)hypoxia and oncogene extracellular matrix( release and activation by extracellular matrix-deg

32、rading proteases )other proangiogenic signals(such as FGF) angiogenesis inhibitors TSP-1 binds transmembrane receptors displayed by endothelial cells and thereby evokes suppressive signals that can counteract proangiogenic stimuli Angiostatin Proteolytic cleavage of structural proteins Endostatin Ph

33、ysiologic regulators that modulate transitory angiogenesis during tissue remodeling and wound healingPericytes is important for the maintenance of a functional tumor neovasculatureA variety of bone marrow-derived cells contribute to tumor angiogenesis macrophages, neutrophils, mast cells, and myeloi

34、d progenitors, the peri-tumoral inflammatory cells Help to trip the angiogenic switch in previously quiescent tissue Sustain ongoing angiogenesis Protect the vasculature from the effects of drugs targeting therapyActivating Invasion and Metastasisinvasion-metastasis cascadeE-cadherin, a key cell-to-

35、cell adhesion molecule E-cadherin helps to assemble epithelial cell sheets and maintain the quiescence of the cells within these sheets. Increased expression of E-cadherin was well established as an antagonist of invasion and metastasis Increased expression of E-cadherin was well established as an a

36、ntagonist of invasion and metastasis,； reduction of its expression was known to potentiate these phenotype Frequently observed down regulation and occasional mutational inactivation of E-cadherin in human carcinomas provided strong support for its role as a key suppressor of this hallmark capability

37、The epithelial-mesenchymal transition( EMT) Broadly Regulates Invasion and MetastasisMotilityInasivenessResistance to apoptosis EMT：transformed epithelial cells can acquire the abilities to invade, to resist apoptosis, and to disseminate Embryonic morphogenesis and wound healing Carcinoma cells can

38、concomitantly acquire multiple attributes that enable invasion and metastasis. EMT are able to orchestrate most steps of the invasion-metastasis cascademesenchymal-epithelial transition (MET) MET results in the formation of new tumor colonies of carcinoma cells exhibiting a histopathology similar to

39、 those of carcinoma cells in the primary tumorContributions of Stromal Cells to Invasionand Metastasis Crosstalk between cancer cells and cells of the neoplastic stroma is involved in the acquired capability for invasive growth and metastasis Mesenchymal stem cells (MSCs) present in the tumor stroma

40、 have been found to secrete CCL5/RANTES in response to signals released by cancer cells; CCL5 then acts reciprocally on the cancer cells to stimulate invasive behavior Macrophages at the tumor periphery can foster local invasion by supplying matrix-degrading enzymes such as metalloproteinases and cy

41、steine cathepsin proteases Emerging hallmarksGenome Instability and Mutation Gene disorders Multiple hallmarks depends in large part on a succession of alterations in the genomes of neoplastic cells. Multistep tumor progression can be portrayed as a succession of clonal expansions, each of which is

42、triggered by the acquisition of an enabling mutant genotype. Cancer cells often increase the rates of mutation The accumulation of mutations can be accelerated by compromising the surveillance systems that normally monitor genomic integrity and force genetically damaged cells into either senescence

43、or apoptosis The role of TP53 is central guardian of the genomeA diverse array of defects of theDNA-maintenance machinery-caretakers of the genome Detect-ing DNA damage and activating the repair machinery Directly repairing damaged DNA Inactivating or intercepting mutagenic molecules before they hav

44、e damaged the DNATumor-Promoting Inflammation Virtually every neoplastic lesion contains immune cells Historically, such immune responses were largely thought to reflect an attempt by the immune system to eradicate tumors Antitumoral responses By 2000, there were already clues that the tumor-associa

45、ted inflammatory response had the unanticipated, paradoxical effect of enhancing tumorigenesis and progressionContribution of inflammation to cancer cells Supplying bioactive molecules to the tumor microenvironment :growth factors; survival factors ; proangiogenic factors,et al. Is demonstrably capa

46、ble of fostering the development of incipient neoplasias into full-blown cancers Release chemicals, notably reactive oxygen species, that are actively mutagenic for nearby cancer cells, accelerating their genetic evolution toward states of heightened malignancyReprogramming Energy Metabolism Under aerobic conditions, normal cells process glucose,first to pyruvate via glycolysis in the cytosol and thereafter to carbon dioxide in the mitochondria; under anaerobic conditions, glycolysis is favored Cancer cells can reprogram their glucose metabolism “aerobic glycolysis” Upregulating g